Camphanylidene and phenylalkyl inositol polyphosphate compounds, compositions, and methods of their use

Abstract

This invention relates to new camphanylidene and phenyl alkyl inositol polyphosphate derivatives that inhibit the absorption of sodium ions in epithelial cells and regulate inducible nitric oxide synthase (iNOS) in macrophages. The invention provides methods for inhibiting sodium ion absorption by epithelial cells and/or regulating inducible nitric oxide synthase (iNOS) in macrophages, by treating epithelial cells or administering to a patient in need of such treatment a therapeutically effective amount of camphanylidene and/or phenyl alkyl inositol polyphosphate compound. Representative camphanylidene and phenyl alkyl inositol polyphosphate compounds include, for example, 1,2-camphanylidene-myo-inositol 3,4,5,6-tetrakisphosphate octalkis (propionoxymethyl) ester (INO-4996), 2,3-camphanylidene-myo-inositol 1,4,5,6-tetrakisphosphate octakis (propionoxymethyl) ester (INO-4984) and 2-O-butyryl-1-O-(3-phenylpropyl)-myo-inositol 3,4,5,6-tetrakisphosphate octakis (propionoxymethyl) ester (INO-4997).

1 . A sodium ion absorption and/or inducible nitric oxide synthase (iNOS) inhibiting camphanylidene or phenyl alkyl inositol polyphosphate compound, or a stereoisomer, racemate, prodrug or a pharmaceutically acceptable salt thereof.  
   
   
       2 . A camphanylidene inositol polyphosphate compound selected from the group consisting of 2,3-camphanylidene-myo-inositol 1,4,5,6-tetrakisphosphate, 1,2-camphanylidene-myo-inositol 3,4,5,6-tetrakisphosphate, and the stereoisomers, racemates, prodrugs, esters and pharmaceutically acceptable salts thereof.  
   
   
       3 . A compound of  claim 2 , which is an ester selected from the group consisting of acetoxymethylesters (AM-esters), propionoxymethylesters (PM-esters) or pivaloyloxymethyl esters.  
   
   
       4 . A compound of  claim 3  selected from the group consisting of 2,3-camphanylidene-myo-inositol 1,4,5,6-tetrakisphosphate octakis (propionoxymethyl) ester, and 1,2-camphanylidene-myo-inositol 3,4,5,6-tetrakisphosphate octakis (propionoxymethyl) ester, and the stereoisomers, racemates, prodrugs, and pharmaceutically acceptable salts thereof.  
   
   
       5 . A method for inhibiting sodium ion absorption by epithelial cells, comprising treating the cells with an effective amount of a sodium uptake inhibiting camphanylidene and/or phenyl alkyl inositol polyphosphate compound.  
   
   
       6 . A method for inhibiting sodium ion absorption by epithelial cells in a human or animal patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a sodium uptake inhibiting camphanylidene and/or phenyl alkyl inositol polyphosphate compound.  
   
   
       7 . A method of  claim 6 , wherein the sodium uptake inhibiting camphanylidene and/or phenyl alkyl inositol polyphosphate compound is a sodium uptake inhibiting inositol polyphosphate compound.  
   
   
       8 . A method of  claim 6 , wherein the camphanylidene inositol polyphosphate compound is selected from the group consisting of 2,3-camphanylidene-myo-inositol 1,4,5,6-tetrakisphosphate, 1,2-camphanylidene-myo-inositol 3,4,5,6-tetrakisphosphate, and the stereoisomers, racemates, prodrugs, esters and a pharmaceutically acceptable salts thereof.  
   
   
       9 . A method of  claim 8 , which is an ester selected from the group consisting of acetoxymethylesters (AM-esters), propionoxymethylesters (PM-esters) or pivaloyloxymethyl esters.  
   
   
       10 . A method of  claim 9  selected from the group consisting of 2,3-camphanylidene-myo-inositol 1,4,5,6-tetrakisphosphate octakis (propionoxymethyl) ester, and 1,2-camphanylidene-myo-inositol 3,4,5,6-tetrakisphosphate octakis (propionoxymethyl) ester, and the stereoisomers, racemates, prodrugs, and pharmaceutically acceptable salts thereof.